Epoxides are frequently formed as metabolites of unsaturated hydrocarbons by cytochrome P-450-dependent monooxygenase activity. Many arene and alkene oxides are known to react covalently with macromolecules and to transform cells in vitro, suggesting they are ultimate carcinogens, mutagens or cytotoxins. We are studying various aspects of the enzymatic formation and subsequent metabolism of epoxides in relationship to cell-selective and organ-selective toxicity of compounds metabolized to epoxides by both hepatic and extrahepatic tissues. Particular attention is given to the respiratory tract because this is a common site for pollutant-mediated damage. We are currently investigating stereochemical aspects of the P-450-dependent oxidation of styrene to styrene 7,8-oxide in microsomal and reconstituted monooxygenase systems, stereochemical and kinetic aspects of the biotransformation of model alkene (styrene 7,8-oxide) and polycyclic arene (benzo(a)pyrene 4,5-oxide) oxide substrates by cytosolic and purified glutathione transferases of diverse origin, the distribution and characteristics of components of the cytochrome P-450-containing monooxygenase system in vascular endothelium and the status of the tripeptide glutathione, which is important in detoxication of electrophilic metabolics, in perfused lung, Clara cells, alveolar type II cells, alveolar macrophages and tracheal cells (mixed) isolated from rabbit lung before and after exposure to electrophilic metabolites or conditions of oxidant stress (e.g., exposure to paraquat).